Azole derivatives, pharmaceutical compositions containing the same, and method for treating mycosis and estrogen-dependent diseases

ABSTRACT

Azole derivatives (including stereoisomers and pharmaceutically acceptable salts) of the formula:   C4 alkyl; R3 is H, OH, CN, halogen, haloalkyl, C1-C4 alkyl or phenyl, and if there are two or more R3 groups, such R3 groups may be the same or different; n is an integer from 0 to 5; Y is N or CH; and X is O, S or NH have antimycotic and aromatase inhibitory activities. Compositions containing the azole derivatives and a method of treating mycosis and estrogen-dependent diseases by administering effective quantities of the azole derivatives are also disclosed.

This is a division of application Ser. No. 07/183,339 filed Jan. 19,1994, which is a division of Ser. No. 08/120,758 filed Sep. 15, 1993,now U.S. Pat. No. 5,407,952, which is a division of Ser. No. 08/067,052filed May 26, 1993, now U.S. Pat. No. 5,324,740.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to azole derivatives, to pharmaceuticalcompositions containing the same, and to a method for treating mycosisor estrogen-dependent diseases.

2. Description of the Related Art

In recent years, the number of opportunistically-infected patients withlow immunologic resistance has been increasing with the medicalprogress.

Opportunistically-infectious mycosis profundus, such as Candidiasis,Aspergillosis, and Cryptococcosis, is occurring in such patients at ahigh rate, and effective countermeasures for such mycosis are becomingmore and more difficult to achieve.

Therefore, research for developing a medicine superior to theconventional antimycotic agents is being actively conducted. Further,research for developing aromatase inhibitors is being conducted also.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel azole derivativesuseful for treating mycosis or for use as aromatase inhibitors.

The present inventors have found that novel azole derivatives having aheterocyclopentane ring have low toxicity and high antimycotic activityper os, as well as having high aromatase inhibitory activity.

The present invention is based on such findings.

According to a first aspect of the present invention, there are providedazole derivatives of the formula (I): ##STR2## and stereoisomersthereof, wherein R₁ and R₂ respectively are H or C₁ -C₄ alkyl; X is O,S, or NH; R₃ is H, OH, CN, halogen, haloalkyl, C₁ -C₄ alkyl, or phenyl,and if there are two or more R₃ groups, such PT groups may be the sameor different; n is an integer from 0 to 5; and Y is N or CH, andpharmaceutically acceptable salts thereof.

According to a second aspect of the present invention, there areprovided pharmaceutical compositions containing the azole derivatives offormula (I).

According to a third aspect of the present invention, there is provideda method of using the azole derivatives of formula (I) to treat mycosisand estrogen-dependent diseases.

The novel azole derivatives of the present invention have low toxicity,antimycotic activity even by oral administration, and aromataseinhibitory activity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds according to the present invention are compounds offormula (I): ##STR3## and stereoisomers thereof; wherein R₁ and R₂ eachare H or C₁ -C₄ alkyl; X is O, S, or NH; R₃ is H, OH, CN, halogen,haloalkyl, C₁ -C₄ alkyl or phenyl, and if there are two or more R₃groups, such R₃ groups may be the same or different; n is an integerfrom 0 to 5; and Y is N or CH, and pharmaceutically acceptable saltsthereof.

The novel compounds of formula (I) can be prepared by:

a) reacting compounds of formula (V) ##STR4## wherein R₁ and R₂respectively are H or C₁ -C₄ alkyl; X is O, S, or NH; and R is alkyl,with compounds of formula (IV') ##STR5## wherein R₃ is H, OH, CN,halogen, haloalkyl, C₁ -C₄ alkyl or phenyl, and if there are two or moreR₃ groups, such R₃ group may be the same or different; Z is a leavinggroup; and n is an integer from 0 to 5, thereby obtaining compounds offormula (IV) ##STR6## wherein R, R₁, R₂, R₃, X, and n have the samemeaning as described in formulae (V) and (I),

b) subjecting the compounds o f formula (IV) todecarboxylation, therebyobtaining compounds of formula (III): ##STR7## wherein R₁, R₂, R₃, X,and n are defined the same as in formulae (V) and (I),

c) reacting the compounds of formula (III) with sulfur ylide, therebyobtaining compounds of formula (II): ##STR8## wherein R₁, R₂, R₃, X, andn have the same meaning as in formulae (V) and (I), and

d) reacting the compounds of formula (II) with compounds of formula(II'): ##STR9## wherein Y is N or CH; and M is a metal ion, therebyobtaining the compounds of formula (I).

In formulae (I), (II), (II'), (III), (IV), (IV')and (V), the C₁ -C₄alkyl of R₁, R₂, and R₃ includes methyl, ethyl, straight-chain orbranched-chain propyl, or straight-chain or branched-chain butyl.

Halogen of R₃ and Z includes,for example, Cl, Br, I, and F.

Alkyl of R preferably is a C₁ -C₄ alkyl, for example, methyl, ethyl,straight-chain or branched-chain propyl, or straight-chain orbranched-chain butyl.

Haloalkyl is alkyl substituted with halogen such as Cl, Br, I, or F.

The metal ion of formula (II') includes Na, K, and other monovalentmetal ions.

Examples of suitable diluents which can be used in a series of reactionsin steps (a), (b), (c), and (d) for preparing the-azole derivatives offormula (I) are: hydrocarbons, such as benzene, toluene, xylene, andhexane; halohydrocarbons, such as methylene chloride, chloroform, andcarbon tetrachloride; alcohols, such as methanol, ethanol, andisopropanol; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, and dioxane; acetonitrile; acetone; dimethylformamide;dimethyl sulfoxide; and ethyl acetate.

The reactions in steps (a), (b), (c), and (d) may be carried out in thepresence of a base or an acid in addition to the above-mentioneddiluent.

Examples of the base that can be used herein are: alkali metalcarbonates, such as sodium carbonate and potassium carbonate; alkalimetal hydroxides, such as sodium hydroxide and potassium hydroxide;alkali metal alcoholates, such as sodium methylate, sodium ethylate andpotassium tertiary butyrate; alkali metal hydrides such as sodiumhydride and potassium hydride; alkyl compounds of alkali metals, such asn-butyl lithium; and other bases, such as triethylamine and pyridine.

Examples of the acid used in the described process are: inorganic acids,such as hydrochloric acid, hydrobromic acid, hydroiodic acid, andsulfuric acid; and organic acids such as formic acid, acetic acid,butyric acid, and p-toluenesulfonic acid.

The cyclopentanone carboxylate derivatives of formula (V) used as astarting material in step (a) can be obtained by the method disclosed byM. A. Gianturco in Tetrahedron, 20, 1763, 1964.

In step (a):

The cyclopentanone carboxylate derivatives of formula (V) aresubstituted by a desirable benzyl group to obtain the cyclopentanonecarboxylate compounds of formula (IV). The compounds of formula (V) aredissolved in the diluent above and, if necessary, in the presence of abase, reacted with benzyl derivatives.

The reaction temperature is preferably in the range of -30° to 120° C.,and more preferably, in the range of 0° to 100° C.

The reaction period is preferably in the range of 1 to 190 hours, andmore prferably in the range of 5 to 160 hours.

The cyclopentanone carboxylate compounds of formula (IV) include twooptical isomers of formulae (IRA) and (IVA') below. ##STR10##

In step (b):

The cyclopentanone carboxylate compounds of formula (IV) are refluxedwith inorganic acids or organic acids as mentioned above, hydrolyzed,and decarboxylated to obtain the cyclopentanone compounds of formula(III).

The reaction period is preferably in the range of 1 to 24 hours, andmore preferably, in the range of 2 to 12 hours.

The cyclopentanone compounds of formula (III) include two opticalisomers of formula (IIIA) and (IIIA') below. ##STR11##

In step (c):

The cyclopentanone compounds of formula (III) are dissolved in thediluent above and reacted with sulfur ylide to obtain the oxiranecompounds of formula (II).

The reaction temperature is preferably in the range of -10° to 130° C.,and more preferably, in the range of 5° to 100° C. The reaction periodis preferably in the range of 0.1 to 8 hours, and more preferably in therange of 0.2 to 4 hours.

The sulfur ylide can be obtained as follows. Trimethylsulfoxonium iodideis dissolved in dimethyl sulfoxide at room temperature, and sodiumhydride washed with hexane is added to the solution at room temperatureto obtain sulfur ylide with evolution of hydrogen gas.

The oxirane compounds of formula (II) obtained in step (c) include fouroptical isomers of formulae (IIA), (IIA'), (IIB), and (IIB'). ##STR12##

The oxirane compounds of formula (II) are reacted with solutions ofsodium salts of 1H-1,2,4-triazole or sodium salts of imidazole offormula (II') in a diluent to obtain the azole compounds of formula (I).

That is, to the solutions of sodium salts of 1H-1,2,4-triazole or sodiumsalts of imidazole of formula (II) in a diluent, a base is added ifnecessary, and then oxirane compounds of formula (II) are added.Alternatively, oxirane compounds of formula (II) may be dissolved firstin the diluent, followed by adding alkali metal salts of1H-1,2,4-triazole or alkali metal salts of imidazole.

The reaction temperature is preferably in the range of 10° to 120° C.,and, more preferably, in the range of 20° to 100° C.

The reaction period is in the range of 0.1 to 10 hours, preferably inthe range of 0.3 to 5 hours.

The resulting solution is cooled and extracted with an organic solvent,such as ethyl acetate, chloroform, methylene chloride or benzene, whilebeing placed in ice-cold water. The resultant layer of organic solutionis collected.

The collected organic solution is washed with water, and the solvent isremoved by evaporation under reduced pressure.

The obtained residue is recrystallized or chromatographed forpurification to obtain the azole compounds of formula (I).

The azole compounds of formula (I) have optical isomers of formula (IA),(IA'), (IB) , and (IB'). ##STR13##

Representative azole derivatives of formula (I) of the present inventionare shown in Tables 1 to 7. Each compound in Tables 1 to 7 has thestructures of formulae (IA) and (IA') above, wherein: Me is methyl; Etis ethyl; iPr is isopropyl; Bu is n-butyl; t-Bu is t-butyl; and Ph isphenyl.

Novel compounds of formulae (I), (II), (III), (IV), and (V) may possiblyhave two or three different substituents that have replaced hydrogenatoms of the heterocyclopentane ring and, therefore, have stereoisomers.The present invention includes each of such stereoisomers and a mixturethereof.

Separation of the stereoisomers above can be carried out by means ofordinary methods such as chromatography or recrystallization.

The novel azole derivatives of formula (I) may be used in the form ofpharmaceutically acceptable salts thereof.

The evaluation of antimycotic activity can be carried out byadministering a dosage of the compound in the tail vein of mice thathave been inoculated with a strain of Candida albicans, preferablyorally, and observing the mortality of the inoculated mice for 20 days.

The survival rate was calculated from the mean survival days.

The azole derivatives of formula (I) have antimycotic activity and areuseful for treating mycosis. For example, these azole derivatives areuseful for treating local mycosis of humans caused by fungi of thegenera such as Candida, Trichophyton, Microsporum, and Epidermophyton ormucosal mycosis caused by Candida albicans, e.g., oral- andvaginal-Candidiasis.

The azole derivatives of formula (I) can also be used for treatingsystemic mycosis caused by Candida albicans, Cryptococcus neoformans,Aspergillus fumigatus or fungi of the genera such as Coccidioides,Paracoccidioides, Histoplasma, and Blastomyces.

The aromatase enzyme-inhibitory activity was determined in the mannerdescribed by Covey, D. F., Biochem. Biophys. Res. Commu., 157 (1),81-86, 1988. More specifically, the aromatase-inhibitory activity of acompound of formula (I) was evaluated in terms of the concentration(IC₅₀) of the compound causing 50% inhibition of the aromatase activity.

The IC₅₀ values of the azole compounds (I) did not exceed 7×10⁻⁶ M.

Thus, the azole compounds (I) of the present invention are useful asaromatase inhibitors.

The aromatase aromatizes the A ring of steroid hormones. Theproliferation of tumors, such as breast cancer, prostatic cancer,ovarian cancer, uterine tumor, pancreatic carcinoma, endometriosis,polycystic ovarian disease, benign breast disease, and Cushing'ssyndrome, depends upon steroid hormones having the A ring, particularly,estrogen.

Therefore, the azole derivatives of formula (I) havingaromatase-inhibitory activity are useful for treating various tumors,namely the compounds of formula (I) are useful as antitumor agents.

The azole derivatives of formula (I) may be used alone. However, theyare generally administered in the form of a mixture with carriers and/ordiluents selected in accordance with the routes of administration andthe methods of standard preparations.

The azole derivatives of formula (I) are administered in an amount of0.001 to 300 mg/kg of patient body weight per day, orally orparenterally, and preferably, in the range of 0.01 to 100 mg/kg.

The above doses are for average cases and there exist cases which gobeyond the above range. Such cases are included within the scope of thisinvention.

The azole derivatives of the present invention are administered to apatient from one to four times per day.

                  TABLE 1                                                         ______________________________________                                        Comp. No. R.sub.1                                                                              R.sub.2  R.sub.3                                                                            n     X    Y                                   ______________________________________                                         1        Me     H        4-F  1     O    N                                    2        Me     H        4-F  1     O    CH                                   3        Me     H        4-F  1     S    N                                    4        Me     H        4-F  1     S    CH                                   5        Me     H        4-F  1     NH   N                                    6        Me     H        4-F  1     NH   CH                                   7        Me     H        2-F  1     O    N                                    8        Me     H        2-F  1     O    CH                                   9        Me     H        2-F  1     S    N                                   10        Me     H        2-F  1     S    CH                                  11        Me     H        2-F  1     NH   N                                   12        Me     H        2-F  1     NH   CH                                  13        Me     Me       4-F  1     O    N                                   14        Me     Me       4-F  1     O    CH                                  15        Me     Me       4-F  1     S    N                                   16        Me     Me       4-F  1     S    CH                                  17        Me     Me       4-F  1     NH   N                                   18        Me     Me       2-F  1     O    N                                   19        Me     Me       2-F  1     S    N                                   20        Me     Me       2-F  1     NH   N                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Comp. No. R.sub.1                                                                              R.sub.2  R.sub.3                                                                            n     X    Y                                   ______________________________________                                        21        H      H        4-F  1     O    N                                   22        H      H        4-F  1     O    CH                                  23        H      H        2-F  1     O    N                                   24        H      H        2-F  1     O    CH                                  25        H      H        4-F  1     S    N                                   26        H      H        4-F  1     S    CH                                  27        H      H        2-F  1     S    CH                                  28        H      H        2-F  1     NH   N                                   29        H      H        4-Cl 1     O    N                                   30        H      H        4-Cl 1     S    N                                   31        H      H        2-Cl 1     O    CH                                  32        H      H        2-Cl 1     S    N                                   33        Me     Me       4-Cl 1     O    N                                   34        Me     Me       4-Cl 1     O    CH                                  35        Me     Me       4-Cl 1     S    N                                   36        Me     Me       4-Cl 1     S    CH                                  37        Me     Me       2-Cl 1     O    N                                   38        Me     Me       2-Cl 1     O    CH                                  39        Me     Me       2-Cl 1     NH   N                                   30        Me     Me       2-Cl 1     NH   CH                                  ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Comp. No. R.sub.1                                                                              R.sub.2  R.sub.3                                                                             n     X    Y                                  ______________________________________                                        41        Me     Me       2,4-F.sub.2                                                                         2     O    N                                  42        Me     Me       2,4-F.sub.2                                                                         2     O    CH                                 43        Me     Me       2,4-F.sub.2                                                                         2     S    N                                  44        Me     Me       2,4-F.sub.2                                                                         2     S    CH                                 45        Me     Me       2,4-F.sub.2                                                                         2     NH   N                                  46        Me     Me       2,4-F.sub.2                                                                         2     NH   CH                                 47        Me     Me       2,4-Cl.sub.2                                                                        2     O    N                                  48        Me     Me       2,4-Cl.sub.2                                                                        2     O    CH                                 49        Me     Me       2,4-Cl.sub.2                                                                        2     S    N                                  50        Me     Me       2,4-Cl.sub.2                                                                        2     S    CH                                 51        Me     Me       2,4-Cl.sub.2                                                                        2     NH   N                                  52        Me     Me       2,4-Cl.sub.2                                                                        2     NH   CH                                 53        Me     Me       4-CN  1     O    N                                  54        Me     Me       4-CN  1     O    CH                                 55        Me     Me       4-CN  1     S    N                                  56        Me     Me       4-CN  1     S    CH                                 57        Me     Me       4-CN  1     NH   N                                  58        Me     Me       4-CN  1     NH   CH                                 59        Me     Me       2-CN  1     O    N                                  60        Me     Me       2-CN  1     S    CH                                 ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Comp. No R.sub.1                                                                              R.sub.2 R.sub.3                                                                              n     X    Y                                   ______________________________________                                        61       Me     Me      2,4-(CN).sub.2                                                                       2     O    N                                   62       Me     Me      2,4-(CN).sub.2                                                                       2     O    CH                                  63       Me     Me      2,4-(CN).sub.2                                                                       2     S    N                                   64       Me     Me      2,4-(CN).sub.2                                                                       2     S    CH                                  65       Me     Me      2,4-(CN).sub.2                                                                       2     NH   N                                   66       Me     Me      2,4-(CN).sub.2                                                                       2     NH   CH                                  67       Me     Me      2-Ph   1     O    N                                   68       Me     Me      2-Ph   1     O    CH                                  69       Me     Me      2-Ph   1     S    N                                   70       Me     Me      2-Ph   1     S    CH                                  71       Me     Me      2-Ph   1     NH   N                                   72       Me     Me      2-Ph   1     NH   CH                                  73       Me     Me      4-Ph   1     O    N                                   74       Me     Me      4-Ph   1     O    CH                                  75       Me     Me      4-Ph   1     S    N                                   76       Me     Me      4-Ph   1     S    CH                                  77       Me     Me      4-Ph   1     NH   N                                   78       Me     Me      4-Ph   1     NH   CH                                  79       H      Me      4-F    1     O    N                                   80       H      Me      4-F    1     O    CH                                  ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Comp. No. R.sub.1                                                                              R.sub.2  R.sub.3                                                                            n     X    Y                                   ______________________________________                                        81        H      Me       4-F  1     S    N                                   82        H      Me       4-F  1     NH   CH                                  83        H      Me       2-F  1     O    N                                   84        H      Me       2-F  1     S    CH                                  85        H      Me       2-F  1     NH   N                                   86        Et     H        4-F  1     O    N                                   87        Et     H        4-F  1     S    N                                   88        Et     H        4-F  1     NH   CH                                  89        Et     H        2-F  1     O    CH                                  90        Et     H        2-F  1     S    N                                   91        Et     H        2-F  1     NH   CH                                  92        H      Et       4-F  1     O    CH                                  93        H      Et       4-F  1     S    N                                   94        H      Et       2-F  1     NH   N                                   95        H      Et       2-F  1     NH   CH                                  96        Pr     H        4-F  1     O    N                                   97        iPr    H        4-F  1     O    CH                                  98        Pr     H        4-F  1     S    N                                   99        Pr     H        2-F  1     O    N                                   100       Pr     H        2-F  1     S    CH                                  ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Comp. No. R.sub.1                                                                              R.sub.2  R.sub.3                                                                             n     X    Y                                  ______________________________________                                        101       Pr     H        2-F   1     NH   N                                  102       iPr    H        2,4-F.sub.2                                                                         2     O    N                                  103       Pr     H        2,4-F.sub.2                                                                         2     S    CH                                 104       Pr     H        2,4-F.sub.2                                                                         2     NH   N                                  105       H      Pr       4-F   1     O    CH                                 106       H      Pr       4-F   1     S    N                                  107       H      iPr      4-F   1     NH   CH                                 108       H      Pr       2-F   1     O    CH                                 109       H      iPr      2-F   1     S    N                                  110       H      Pr       2,4-F.sub.2                                                                         2     O    CH                                 111       H      iPr      2,4-F.sub.2                                                                         2     S    N                                  112       H      Pr       2,4-F.sub.2                                                                         2     NH   CH                                 113       Bu     H        4-F   1     O    N                                  114       Bu     H        4-F   1     S    CH                                 115       Bu     H        4-F   1     NH   N                                  116       tBu    H        2-F   1     O    N                                  112       Bu     H        2-F   1     S    CH                                 118       tBu    H        2-F   1     NH   N                                  119       Bu     H        2,4-F.sub.2                                                                         2     O    N                                  120       Bu     H        2,4-F.sub.2                                                                         2     S    CH                                 ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Comp. No. R.sub.1                                                                              R.sub.2  R.sub.3                                                                             n     X    Y                                  ______________________________________                                        121       Bu     H        2,4-F.sub.2                                                                         2     NH   N                                  122       H      Bu       4-F   1     O    N                                  123       H      tBu      4-F   1     O    CH                                 124       H      Bu       4-F   1     S    N                                  125       H      tBu      4-F   1     NH   N                                  126       H      Bu       2-F   1     O    N                                  127       H      Bu       2-F   1     S    CH                                 128       H      tBu      2-F   1     NH   N                                  129       H      Bu       2,4-F.sub.2                                                                         2     O    CH                                 130       H      tBu      2,4-F.sub.2                                                                         2     O    N                                  131       H      Bu       2,4-F.sub.2                                                                         2     S    CH                                 132       H      Bu       2,4-F.sub.2                                                                         2     NH   N                                  133       H      Bu       2,4-Cl.sub.2                                                                        2     O    N                                  134       H      Bu       2,4-Cl.sub.2                                                                        2     S    CH                                 135       H      Bu       2,4-Cl.sub.2                                                                        2     NH   CH                                 136       H      tBu      4-Cl  1     O    N                                  137       H      Bu       4-Cl  1     S    CH                                 138       H      Bu       2-Cl  1     O    N                                  ______________________________________                                    

EXAMPLES

The present invention is illustrated by specific examples. However, thisis not intended to limit the scope of the present invention in any way.In the following examples, elemental analysis was carried out bydetecting the decomposed gas of the compounds with a TCD detector in anautomatic elemental analyzer (MT3; manufactured by YANAGIMOTOSEISAKUSHO). The optical rotation [α]_(D) was determined with anautomatic spectropolarimeter (DIP-360; manufactured by NIHON BUNKO CO.).

The NMR spectra were recorded in ppm on a JNM-GSX spectrometer(manufactured by NIHON DENSHI CO.) in CDCl₃ relative to Me₄ Si.

The IR spectrum was measured with a spectrophotometer (A-202;manufactured by NIHON BUNKO CO.) using a KBr or neat method and V_(max)was determined.

Thin layer chromatography was performed with n-hexane-ethyl acetate orethyl acetate to measure Rf.

Further, mp was measured with a micro melting point detector(manufactured by YANAGIMOTO SEISAKUSHO).

Example 1 [1] Synthesis of4-carbomethoxy-4-(4-fluorobenzyl)-2-methyl-tetrahydrofuran-3-one (4-1)

Sodium hydride (0.25 g, 10.5 mmol) was suspended in freshly distilledtetrahydrofuran (10 ml) and the suspension was stirred on a water bath.A solution of 4-carbomethoxy-2-methyltetrahydrofuran-3-one (5-1) (1.58g, 10 mmol) in distilled tetrahydrofuran (10 ml) was added dropwise tothe suspension and stirred for 30 min. 4-Fluorobenzylbromide (2.08g,11.0mmol) was added dropwise to the suspension and stirred overnight.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold waterand extracted with diethyl ether.

The organic layer was washed with brine and dried over anhydrous sodiumsulfate. The dried solution was concentrated under reduced pressure toobtain a crude product (2.87g). The crude product was chromatographed ona silica gel column with n-hexane-ethyl acetate (4:1) to obtain thetitle compound as a colorless liquid (4-1) (2.13 g, 80.4%).

The physicochemical properties of the liquid are as follows:

Rf: 0.46 (n-hexane-ethyl acetate = 2: 1) IR(V_(max), cm⁻¹, neat): 3000m,2960m, 2895m, 1765s, 1735s, 1601s, 1520s, 1440s, 1370m, 1261s, 1220s

¹ H-NMR (δppm, CDCl₃): 1.55 (d, 3 H), 1.32 (d, 3 H), 3.06 (d, 1 H), 3.12(d, 1 H), 3.22 (d, 1H), 3.25 (d, 1 H), 3.67 (q, 1 H), 3.91 (d, 1 H),4.00 (q, 1 H), 4.19 (d, 1 H), 4.40 (d, 1 H), 4.58 (d, 1 H), 6.97 (m, 4H), 7.11 (M, 4 H).

[2] Synthesis of 4-(4-fluorobenzyl) -2-methyltetrahydrofuran-3-one (3 -1).

Glacial acetic acid (11 ml) and an aqueous solution of sul furic acid(12.5%, 5 ml ) were added to 4-carbomethoxy-4-(4-fluorobenzyl)-2-methyltetrahydrofuran-3-one (4-1) (1.51 g, 5.6mmol), and the mixture was refluxed for 4 hours under argon.

At the completion of the reaction, which had been confirmed by thinlayer chromatography, the resulting solution was poured into ice-coldwater and extracted with diethyl ether.

The organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a crudeproduct (1.55g). The crude product was purified by silica gel columnchromatography using n-hexane-ethyl acetate (2:1) to obtain the titlecompound as a yellow liquid (3-1 ) (0.97 g, 80.8 % ).

Rf: 0.55 (n-hexane-ethyl acetate = 2: 1) IR (V_(max), cm⁻¹, neat):2975w, 2930w, 2855w, 1758s, 1601w, 1515s, 1220s

¹ H-NMR (δppm, CDCl₃): 1.22 (d, 3H), 1.32 (d, 3H), 2.63 (d, 1H), 2.66(d, 1H), 2.76 (m, 2H), 3.01 (d, 0.5 H), 3.03 (d, 0.5H), 3.10 (d, 0.5H),3.13 (d, 0.5H), 3.67 (t, 1H), 4.31 (t, 1H), 6.97 (m, 4H), 7.11 (m, 4H).

[3] Synthesis of 7-(4-fluorobenzyl)-2-methyl-1,5-dioxaspiro [2.4]heptane (2-1)

Trimethylsulfoxonium iodide (0.57 g, 2.2 mmol) was dissolved in dimethylsul foxide (4 ml), and sodium hydride (0.06 g, 2.4 mmol) was added tothe solution being stirred at 10° C. The solution was warmed to roomtemperature, stirred for 30 minutes, after which the solution was cooledto 10° C. 4-(4-Fluorobenzyl)-2-methyl-tetrahydrofuran-3-one (3-1) (0.42g, 2.0 mmol) was added to the solution dropwise, which was then warmedto room temperature, and stirred for 30 minutes.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was added into ice-cold water andextracted with diethyl ether.

The organic layer was washed with brine and dried over anhydrous sodiumsulfate.

The dried solution was concentrated under reduced pressure to obtain acrude product as a yellow liquid having the structures of formulae (IIA)and (IIA') above (2-1) (0.32 g, 72.7%).

Rf: 0.33 (n-hexane-ethyl: acetate = 2:1).

[4] Synthesis of 4-(4-fluorobenzyl)-3-hydroxy-2-methyl-3-(1H-1,2,4-triazol-1-ylmethyl) tetrahydrofuran(Compound No. 1)

7-(4-Fluorobenzyl)-2-methyl-1,5-dioxaspiro [2.4] tetrahydrofuran (2-1)having the structures of formulae (IIA) and (IIA') obtained from Example1 [3] (532.3 mg, 2.39 mmol) was dissolved in dimethylformamide (3.0 ml).Sodium salt of 1H-1,2,4-triazole (283.5 mg, 3.11 mmol) was added to thesolution, which was then stirred at 70° C. for 1 hour in an atmosphereof argon.

At the end of the reaction, which had been confirmed by thin layerchromatography, the reaction mixture was poured into ice-cold water (10ml) and extracted with ethyl acetate (50 ml × 2).

The ethyl acetate layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to obtain a crude product (875.5mg).

The crude product was chromatographed on a silica gel (dia. 2.5 cm ×height 10 cm, 15 g) with ethyl acetate to obtain the title product aswhite crystals having the structures of general formulae (IA) and (IA')described above (Comp. No. 1 ) (489.8 mg, 69.9% ).

Rf: 0.28 (ethyl acetate) mp: 106°-108° C. IR (v_(max), cm⁻¹ KBr): 3200s,3160s, 2991s, 2950s, 2880m, 1600m, 1519s, 1440m, 1420m, 1382m, 1275s,1219s, 1200s, 1159s, 1119s, 1030s, 965m, 750s, 680s

¹ H-NMR (Δppm, CDCl₃): 0.91 (d, 3H), 2.3-2.6 (m, 3H), 3.65 (t, 1H), 3.79(t, 1H), 3.8-3.9 (m, 1H), 4.16 (d, 1H), 4.20 (d, 1H), 6.97 (m, 2H), 7.10(m,2H), 7.97 (2, 1H), 8.09 (s, 1H).

[5] Synthesis of 4-(4-fluorobenzyl)-3-hydroxy-3-(imidazol-1-ylmethyl)-2-methyltetrahydrofuran (Comp. No. 2)

7-(4-Fluorobenzyl)-2 -methyl-1,5-dioxaspiro[2.4]heptane having thestructures of general formulae (IIA) and (IIA') (2-1) (0.32 g, 1.4 mmol)was dissolved in dimethylformamide (3.0 ml). Sodium salt of imidazole(0.17 g, 1.9 mmol ) was added to the solution, which was then stirred at70° C. in an atmosphere of argon for 1 hour. At the end of the reaction,which had been confirmed by thin layer chromatography, the resultingsolution was added to ice-cold water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a crudeproduct as white crystals having the structures of general formulaeabove (IA) and (IA') (Comp. No. 2) (0.56 g).

mp: 114°-118° C. IR (V_(max), cm⁻¹, KBr): 3400s, 3100s, 2980s, 2940s,2860m, 1515s, 1435m, 1270m, 1210s, 1107s, 1075s, 1022s, 820s, 760s,665s,

¹ H-NMR (δppm, CDCl₃): 0.95 (d, 3H), 2.4-2.5 (m, 3H), 3.64 (t, 1H), 3.80(t, 1H), 3.92 (d, 1H), 3.96 (d, 1H), 6.96 (m, 3H), 7.07 (m, 3H), 7.51(s, 1H).

Example 2 [1] Synthesis of4-carbomethoxy-2,2-dimethyltetrahydrofuran-3-one (5-13)

n-Hexane-washed sodium hydride (1.2 g, 50 mmol) and ether (30 ml) wereplaced in a 200 ml round-bottomed flask. Methyl α-hydroxy-isobutyrate(5.95g, 50 mmol) was slowly dripped into the suspension at 0° C.Hydrogen gas was vigorously generated by exothermic reaction. Theresulting solution was stirred at room temperature for 10 minutes,followed by removing ether under reduced pressure with an evaporator.Dimethyl sulfoxide (20 ml) was added to the dried residue immediatelyfollowed by adding methyl acrylate (4.73 g, 55 mmol) all at once.

As a result, the suspension gradually turned to light yellow.

The resulting solution was stirred at room temperature for 15 minutesand then the reaction was stopped with a 5 N-HCl aqueous solution (100ml).

The reaction mixture was extracted with ether (100 ml × 2). The etherlayers were washed with distilled water and dried over anhydrous sodiumsulfate. The solvent was removed by evaporation using an evaporator toobtain a light yellow oil (8.09 g), followed by vacuum distillation (5mmHg) to obtain the title compound as a colorless oil (5-13) (4.77 g,55.5%).

Rf: 0.48 (n-hexane-ethyl acetate = 2: 1) bp: 61°14 63° C./5 mmHg IR(V_(max), cm⁻¹, neat): 3000m, 2950m, 1770s, 1735s, 1420m, 1322m, 1170m

¹ H-NMR (δppm, CDCl₃):

1.28 (s, 3H), 1.29 (s, 3H), 3.58 (t, 1H) ,

3.78 (s, 3H), 4.39 (d, 1H), 4.73 (d, 1H)

[2] Synthesis of 4-carbomethoxy-4-(4-fluorobenzyl )-2,2-dimethyl-tetrahydrofuran-3-one (4-13).

n-Hexane-washed sodium hydride (114.0 mg, 6.0 mmol) was suspended infreshly distilled tetrahydrofuran (10 ml), and4-carbomethoxy-2,2-dimethyltetrahydrofuran-3-one (5-13) (861.0 mg, 10.0mmol) was dripped into the suspension at 0° C. over a period of at least5 minutes.

The reaction was exothermic and hydrogen gas was generated. In about 2minutes, the reaction mixture turned to a light yellow solution. Afterthe solution had been stirred for about 30 minutes,4-fluorobenzylbromide (1.98 g. 10.5 mmol) was added to the solution at0° C. The solution was stirred for 72 hours at 25° C., followed byadding distilled water (20 ml) and extracting the solution with ether(50 ml × 2). The ether layers were washed with brine and with distilledwater, and then dried over anhydrous sodium sulfate. The solvent wasremoved by using an evaporator to obtain a crude product (2.89 g).

The crude product was chromatographed on a silica gel column (dia. 2.5cm × height 8.0 cm, 10 g) with n-hexane-ethyl acetate (4:1) to obtainthe title product as a colorless liquid (4-13) (1.33 g, 94.7%).

Rf: 0.54 (n-hexane-ethyl acetate = 2.1) IR (V_(max), cm⁻¹, neat): 3000m,2975m, 2900m, 17708, 17308, 1610m, 1520s

¹ H-NMR (δppm, CDCl₃): 0.96 (s, 3H), 1.28 (s, 3H), 3.12 (d, 1H), 3.22(d, 1H), 3.75 (s, 3H), 4.02 (d, 1H), 4.49 (d, 1H), 6.96 (t, 2H), 7.12(m, 2H)

[3] Synthesis of 4-(4-fluorobenzyl)-2,2-dimethyltetrahydrofuran-3-one(3-13).

Glacial acetic acid (9 ml) and an aqueous solution of sulfuric acid(12.5%, 5 ml) were added to4-carbomethoxy-4-(4-fluorobenzyl)-2,2-dimethyltetrahydrofuran-3-one(4-13) (1.32 g, 4.7 mmol). The mixture was refluxed in an atmosphere ofargon for 4 hours.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold waterand extracted with diethyl ether.

The organic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a .crudeproduct (1.32 g). The crude product was chromatographed on a silica gelcolumn with n-hexane-ethyl acetate (2:1) to obtain the title product asa yellow libaid (3-13) (0.99 g, 94.7%).

Rf: 0.52 (n-hexane-ethyl acetate = 2: 1) IR (v_(max), cm⁻¹, neat):3010m, 2960m, 2900m, 1762s, 1610m, 1522s

¹ H-NMR (δppm, CDCl₃): 1.10 (s, 3H), 1.27 (s, 3H), 2.69 (dd, 1H), 2.81(m, 1H), 3.08 (dd, 1H), 3.77 (t, 1H), 4.19 (t, 1H), 6.97 (t, 2H), 7.11(t, 2H).

[4 ] Synthesis of 7 - (4 -fluorobenzyl )-4,4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-13 )

Trimethylsulfoxonium iodide (0.22 g, 1.3 mmol) was dissolved in dimethylsul foxide (2 ml ) at room temperature. While stirring the solution at10° C., sodium hydride (0.03 g, 1.2 mmol) was added.

The solution was warmed to room temperature, stirred for 40 minutes, andagain cooled to 10° C. While stirring the solution, 4-(4-fluorobenzyl)-2,2-dimethyl-tetrahydrofuran-3-one (3-13) (0.22 g, 1.0 mmol) was added.The solution was stirred for 10 minutes, warmed to room temperature, andagain stirred for 35 minutes. Ice-cold water was then added to cease thereaction.

The resulting solution was extracted with diethyl ether. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.

The dried solution was concentrated under reduced pressure to obtain acrude product as a light yellow liquid (2-13) having the structures ofgeneral formulae (IIA) and (IIA') above (0.19 g, 82.6%).

Rf: 0.49 (n-hexane-ethyl acetate = 2:1).

[5] Synthesis of 4-(4-fluorobenzyl)-3-hydroxy-2,2-dimethyl-3(1H-1,2,4-triazole-1-ylmethyl) tetrahydrofuran (Compound No. 13)

7-(4-Fluorobenzyl)-4,4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-13 )having the structures of general formukae (IIA) and (IIA') above (106.2mg, 0.45 mmol) was dissolved in dimethylformamide (3 ml). Sodium salt of1H-1,2,4-triazole (53.2 mg, 0.58 mmol) was added to the solution at roomtemperature, and the solution was then stirred at 70° C. in anatmosphere of argon for 1 hour.

At the end of the reaction, the resulting solution was poured intoice-cold water (5 ml) and extracted with diethyl ether (30 ml × 2).

The organic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a crudeproduct (103.3 mg).

The crude product was chromatographed on a silica gel column (dia. 2.5cm × height 2.8 cm, 3.9 g) with ethyl acetate to obtain the titleproduct as white crystals having the structures of general formulae (IA)and (IA') above (Compound No. 13) (68.4 mg, 49.5%).

Rf: 0.28 (ethyl acetate) mp: 123°-124 ° C. IR (v_(max), cm⁻¹, KBr):3400m, 3220m, 3160m, 2950s, 1601s, 1519s, 1219

¹ H-NMR (δppm, CDCl₃): 0.89 (s, 3H) , 1.28 (s, 3H) , 2.47 (m, 1H), 2.60(m, 2H), 3.63 (t, 1H), 3.86 (t, 1H), 4.21 (q, 2H), 6.95 (m, 2H),=7.05(m, 2H), 7.96 (s, 1H), 8.22 (s, 1H).

[6] Synthesis of4-(4-fluorobenzyl)-3-hydroxy-3-(imidazol-1-ylmethyl)-2,2-dimethyltetrahydrofuran(Compound No. 14)

4,4-Dimethyl-7-(4-fluorobenzyl)-1, 5-dioxaspiro[2.4]heptane (2-13)having the structures of general formulae (IIA) and (IIA') above (0.20g, 0.8 mmol) was dissolved in dimethylformamide (3 ml). Sodium salt ofimidazole (0.10 g, 1.1 mmol) was added to the solution, which was thenstirred at 70° C. in an atmosphere of argon for 1 hour.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold waterand extracted with ethyl acetate.

The organic layer was washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a crudeproduct (0.28 g). The crude product was chromatographed on a silica gelcolumn with ethyl acetate. The obtained fraction was furtherrecrystallized from n-hexane-ethyl acetate to obtain the title productas white crystals having the structures of general formulae (IA) and(IA') above (Compound No. 14) (0.11 g, 42.3%).

Rf: 0.08 (ethyl acetate) mp: 159°-162 ° C. IR (v_(max), cm⁻¹, KBr):3430m, 3125m, 3000m, 2900m, 2850m, 1601w, 1518s,

¹ H-NMR (δppm, CDCl₃): 0.95 (s, 3H), 1.27 (s, 3H), 2.37 (dd, 1H), 2.54(dd, 1H), 2.61 (m, 1H), 3.60 (t, 1H), 3.86 (t, 1H), 3.94 (d, 1H), 4.00(d, 1H), 6.96 (m, 2H), 7.06 (m, 4H), 7.61 (s, 1H).

Example 3 [1] Synthesis of4-carbomethoxy-4-(4-chlorobenzyl)-2,2-dimethyltetrahydrofuran-3-one(4-33)

n-Hexane-washed sodiumhydride (240.0 mg, 10.0 mmol) and tetrahydrofuran(10 ml) were placed in an eggplant-shaped flask (50 ml).4-Carbomethoxy-2,2-dimethyltetrahydrofuran-3-one (1.72 g, 10.0 mmol) wasslowly dripped into the suspension at 0° C. over a period of at least 5minutes.

Hydrogen gas was soon generated and the reaction mixture turned to alight yellow solution. The resulting solution was stirred at 0° C. for10 minutes and then 4-chlorobenzyl chloride (1.69 g, 10.5 mmol) wasslowly dripped thereto at 0° C.

The resulting solution was stirred at room temperature for 3 days andthen further stirred at 60° C. for 3 days, which was required because ofthe slow reaction. At the end of the reaction, distilled water was addedto the resulting solution, which was then extracted with ether (100 ml ×2). The ether layers were washed with brine, dried over anhydrous sodiumsulfate, and the solvent was removed by evaporation under reducedpressure to obtain a crude product (3.31 g). The resulting crude productwas chromatographed on a silica gel column (dia. 2.5 cm × height 14 cm,20 g) with n-hexane-ethyl acetate (4:1) to obtain the title product as ayellow liquid above (4-33) (2.43 g, 81.8%).

Rf: 0.40 (n-hexane-ethyl acetate = 2:1) IR (v_(max), cm⁻¹, neat): 3650w,3500w, 2975m, 2950m, 1765s, 1730s, 1595m, 1495s, 1435m, 1408m, 1377m,1360m, 1220s, 1090s, 1012s

¹ H-NMR (δppm, CDCl₃): 0.99 (s, 3H), 1.28 (s, 3H), 3.10 (d, 1H), 3.23(d, 1H), 3.75 (s, 3H), 4.01 (d, 1H), 4.49 (d, 1H), 7.08 (d, 2H), 7.25(d, 2H).

[2] Synthesis of 4-(4-chlorobenzyl)-2,2-dimethyltetrahydrofuran-3-one(3-33)

Glacial acetic acid (8 ml) and an aqueous solution of sulfuric acid(12.5%, 4 ml ) were added to4-carbomethoxy-4-(4-chlorobenzyl)-2,2-dimethyltetrahydrofuran-3-one(4-33) (0.95 g, 3.2 mmol), and the solution was refluxed for 4 hours inan atmosphere of argon.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold waterand extracted with ethyl acetate (50 ml × 2).

The organic layers were washed with brine and dried over anhydroussodium sulfate. The dried solution was concentrated under reducedpressure to obtain a crude product (0.86 g). The crude product wasseparated by silica gel column chromatography using n-hexane-ethylacetate (2:1) to obtain the title product as a yellow liquid (3-33)(0.71 g, 94.0%).

Rf: 0.46 (n-hexane-ethyl acetate = 2:1) IR (v_(max), cm⁻¹, neat): 2990m2948m, 2890m, 1758s, 1600w, 1500s

¹ H-NMR (δppm, CDCl₃): 1.12 (s, 3H), 1.27 (s, 3H), 2.68 (dd, 1H), 2.83(m, 1H), 3.08 (dd, 1H), 3.75 (t, 1H), 4.19 (t, 1H) , 7.09 ( d, 2H) ,7.26 (d, 2H).

[3] Synthesis of 7-(4-chlorobenzyl)-4,4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-33).

Trimethylsulfoxonium iodide (0.29 g, 1.3 mmol) was dissolved in DMSO (2ml). While stirring the solution at 10° C., sodium hydride (0.03 g, 1.2mmol) was added. The solution was warmed to room temperature, stirredfor 30 minutes, and then again cooled to 10° C.

4-(4-Chlorobenzyl)-2,2 -dimethyltetrahydrofuran-3-one (3-33) (0.24 g,1.0 mmol) was added dropwise to the solution, which was then stirred atroom temperature for 30 minutes.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold water(10 ml) and extracted with ethyl acetate (30 ml × 2).

The organic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a crudeproduct as a yellow liquid having the structures of general formulae(IIA) and (IIA') above (2-33) (0.25 g, 96.0%).

Rf: 0.48 (n-hexane-ethyl acetate = 2.1).

[4] Synthesis of4-(4-chlorobenzyl)-3-hydroxy-2,2-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl) tetrahydrofuran (Compound No. 33)

7-(4-Chlorobenzyl)-4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-33 ) havingthe structures of formulae (IIA) and (IIA') above (0.25g, 1.0 mmol) wasdissolved in dimethylformamide (3 ml). Sodium salt of 1H-1,2,4-triazole(0.11 g, 1.3 mmol) was added to the solution, which was then stirred at70° C. in an atmosphere of argon for 1 hour.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold water(10 ml) and extracted with ethyl acetate (30 ml × 2).

The organic layers were washed with brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain a crudeproduct (0.23 g).

The crude product was chromatographed on a silica gel column with ethylacetate, and then the obtained fraction was recrystallized fromn-hexane-ethyl acetate to obtain the title product as white crystalshaving the structures of general formulae (IA) and (IA') above (CompoundNo. 33) (0.06 g, 20%).

Rf: 0.18 (ethyl acetate) mp: 119°-120° C. IR (v_(max), cm⁻¹, KBr):3175s, 2998m, 2950m, 2870m, 1518s, 1498s

¹ H-NMR (δppm, CDCl₃): 0.89 (s, 3H), 1.28 (s, 3H), 2.48 (m, 1H), 2.61(m, 2H), 3.62 (d, 1H), 3.86 (d, 1H), 4.20 (d, 1H), 4.24 (d, 1H), 7.05(m, 2H), 7.24 (m, 2H), 7.96 (s, 1H), 8.21 (s, 1H).

[5] Synthesis of 4-(4-chlorobenzyl)-3-hydroxy-3-(1H-imidazol-l-ylmethyl)-2,2-dimethyltetrahydrofuran (Compound No. 34)

7- (4-Chlorobenzyl) -4,4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-33)having the stereospecific structures of general formulae (IIA) and(IIA') above (0.16 g, 0.6 mmol) was added to dimethyl formamide (3 ml ).Sodium salt of imidazole (0.07 g, 0.8 mmol) was added to the solution,which was then st irred at 70° C. in an atmosphere of argon for 1 hour.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold water(10 ml ) and extracted with ethyl acetate (30 ml × 2). The organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain a crude product (0.21 g).

The crude product was purified by silica gel column chromatography using ethyl acetate. The product was recrystallized from n-hexane-ethylacetate to obtain the title product having the structures of formulae(IA) and (IA') above as white crystals (Compound No. 34) (0.1 g, 46.2%).

Rf: 0.04 (ethyl acetate) mp: 145°-146° C. IR (v_(max), cm⁻¹, KBr):3425m, 3100m, 2975m, 2925m, 2870m, 1618w, 1510w, 1490s,

¹ H-NMR (δppm, CDCl₃): 0.95 (s, 3H), 1.26 (s, 3H), 2.35 (dd, 1H), 2.53(dd, 1H), 2.62 (m, 1H), 3.59 (t, 1H), 3.86 (t, 1H), 3.96 (d, 1H), 4.02(d, 1H), 7.02 (d, 2H), 7.07 (d, 2H), 7.25 (d, 2H), 7.67 (s, 1H).

Example 4

[1]Synthesis of4-carbomethoxy-4-(4-cyanobenzyl)-2,2-dimethyltetrahydrofuran-3-one(4-53)

n-Hexane-washed sodium hydride (120 mg, 5.0 mmol) and tetrahydrofuran(5.0 ml) were placed in an eggplant-shaped flask (50 ml), and then2,2-dimethyl-4-carbomethoxy-tetrahydrofuran-3- one (5-53) (860.7 mg, 5.0mmol) was dropwise added to the suspension at 0° C. In about 2 minutes,the suspension turned into a light yellow solution. After the solutionhad been stirred for 20 minutes, α-bromo-p-tolunitrile (1.03 g, 5.25mmol) was slowly dripped into the resulting solution at 0° C., followedby stirring over night at room temperature.

Distilled water (20 ml) was added to the resulting solution, which wasthen extracted with ether (50 ml × 1, 40 ml × 1).

The ether layers were washed with brine (20 ml × 1) and dried overanhydrous sodium sulfate. The solvent was removed from the driedsolution by using an evaporator to obtain a crude product (1.543 g). Thecrude product was chromatographed on a silica gel column (dia. 2.5 cm ×height 14 cm; 15 g) with n-hexane-ethyl acetate (4:1) to obtain thetitle product as colorless crystals (4-53) (1,324 g, 92.2%).

Rf: 0. 423 (n-hexane-ethyl acetate = 2:1) mp: 65°-65.5 C. IR (v_(max),cm⁻¹, KBr): 2225 (CN), 1775 (CO), 1735. (COOCH₃), 1610m, 1435m, 1219s,980s, 561s,

¹ H-NMR (δppm, CDCl₃): 1.00 (s, 3H), 1.29 (s, 3H), 3.17 (d, 1H), 3.31(d, 1H), 3.76 (s, 3H), 3.98 (d, 1H), 4.50 (d, 1H), 7.28 (d,2H), 7.58 (d,2H).

[2] Synthesis of 4-(4-cyanobenzyl)-2,2-dimethyltetrahydrofuran-3-one(3-53)

2,2 -Dimethyl-4 -carbomethoxy-4-(4-cyanobenzyl)-tetrahydrofuran-3-one(4-53) (305.6 mg, 1 mmol) and glacial acetic acid (2 ml) were placed inan eggplant-shaped flask (25 ml). An aqueous solution of sulfuric acid(1.0 ml, 12.5%) was added to the solution, which was then heated andmaintained at 120° C. for 4.5 hours in an atmosphere of argon.

At the end of the reaction, which had been confirmed by thin layerchromatography, the resulting solution was poured into ice-cold water(30 ml ) and extracted with diethyl ether (50 ml × 1, 40 ml × 1).

The ether layers were washed with brine and dried over anhydrous sodiumsulfate.

The dried solution was concentrated under reduced pressure by using arotary evaporator to obtain a crude product (298.3 mg) . The crudeproduct was chromatographed on a silica gel column (dia. 2.5 cm × height7.0 cm, 10 g) with n-hexane-ethyl acetate (2:1) to obtain the titlecompound in the form of oil (3-53 ) (209.3 mg, 86.3%).

¹ H-NMR (δppm, CDCl₃): 1.13 (s, 3H), 1.28 (s, 3H), 2.77 (dd, 1H), 2.86(m, 1H), 3.17 (dd, 1H), 3.75 (dd, 1H), 4.22 (dd, 1H), 7.29 (d, 2H), 7.59(d, 2H)

IR (v_(max), cm⁻¹, neat): 2225m (CN), 1765s (CO), 1605m, 1510m, 1180mRf: 0.40 (n-hexane-ethyl acetate = 2:1)

[3] Synthesis of7-(4-cyanobenzyl)-4,4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-53)

Trimethylsulfonium iodide (180.4 mg, 0,842mmol) and dimethyl sulfoxide(2.0 ml) were placed in an eggplantshaped flask (25 ml). The solutionwas stirred at 10° C., and n-hexane-washed sodium hydride (18.9 mg,0.785 mmol) was added thereto. The resulting solution was stirred atroom temperature for 30 minutes to obtain a transparent solution.4-(4-Cyanobenzyl)-2,2-dimethyl-tetrahydrofuran-3-one (3-53) (155.9 mg,0.683 mmol) and dimethyl sulfoxide (1.0 ml) were dissolved into thetransparent solution at 10° C. The solution was stirred at roomtemperature for 1 hour. Distilled water was added to the solution tocease the reaction.

The resulting solution was extracted with ether. The ether layer waswashed with brine, and dried over anhydrous sodium sulfate.

The dried solution was concentrated under reduced pressure to obtain acrude product having the structures of formulae (IIA) and (IIA') above(2-53) (121.6 mg).

Rf = 0.40 (n-hexane-ethyl acetate = 2:1).

[4] Synthesis of2,2-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)-3-hydroxy-5-(4-cyanobenzyl)-tetrahydrofuran(Compound No. 53).

The epoxide compound (2-53) (121.6 mg, 0.683 mmol) obtained in step [3 ]above was dissolved in dimethylformamide (3.0 ml), and the sodium saltof 1 H-1,2,4-triazole (80.8 mg, 0.888 mmo1) was added at roomtemperature. The mixture was reacted at 70° C. for 1.5 hours in anatmosphere of argon. At the end of the reaction, which had beenconfirmed by thin layer chromatography, the resulting solution waspoured into ice-cold water (5 ml) and extracted with diethyl ether (50ml × 1, 30 ml × 2).

The organic layers were washed with brine and dried over anhydroussodium sulfate. The solvent was removed by using a rotary evaporator toobtain a crude product (84.3 mg), which was purified by silica gelcolumn chromatography (dia. 1.5 cm × height 4.0 cm, 3 g) using ethylacetate to obtain the title compound (Compound No. 53) (37.2 mg, 17.4%).

mp: 125°-127° C.

¹ H-NMR (δppm, CDCl₃): 1.04 (s, 3H), 1.28 (s, 3H), 2.48 (m, 1H), 2.60(m, 1H) , 2.64 (m, 1H) , 3.16 (t, 1H), 3.84 (t, 1H), 4.23 (d, 1H), 4.27(d, 1H), 7.23 (d, 2H), 7.56 (d, 2H), 7.97 (s, 1H), 8.23 (s, 1H)

[5] Synthesis of2,2-dimethyl-3-(imidazol-1-ylmethyl)-3-hydroxy-5-(4-cyanobenzyl)-tetrahydrofuran(Compound No. 54)

The epoxide compound obtained in Example 4[3] above (2-53) (290 mg, 1.2mmol), dimethylformamide (2.0 ml), and sodium salt of imidazole (145 mg,1.56 mmol) were placed in an eggplant-shaped flask (25 ml), and themixture was stirred at 70° C. for 1.5 hours in an atmosphere of argon.

At the end of the reaction, the reaction mixture was poured intoice-cold water (5 ml) and extracted with diethyl ether (50 ml × 1, 40 ml× 1).

The extraction was extracted with ethyl acetate (250 mg × 2). The ethylacetate layers were washed with brine, and dried over anhydrous sodiumsulfate.

The solvent was removed from the dried solution by evaporation underreduced pressure to obtain a crude product (592.5 mg).

The crude product was chromatographed on a silica gel column (dia. 2.5cm × height 5.0 cm, 7g) with ethyl acetate to obtain the title compound(Compound No. 54) (290.6 mg, 77.8%).

mp: 168°-170° C.

¹ H-NMR (δppm, CDCl₃): 1.27 (s, 3H), 1.29 (s, 3H), 2.29 (d, 1H), 2.63(m, 2H), 3.58 (dd, 1H), 3.80 (dd, 1H), 3.99 (d, 1H), 4.04 (d, 1H), 7.07(s, 1H), 7.13 (s, 1H) 7.16 (d, 7.52 (d, 2H), 7.70 (s, 1H)

IR (v_(max), cm⁻¹, KBr): 3200s, 2210s, 1605s, 1510s, 1220s, 1110s,1080s, 1025s

Example 5 [1] Synthesis of2,2-dimethyl-4-carbomethoxy-4-(2-biphenylmethyl)-tetrahydrofuran-3-one(4-67)

n-Hexane washed sodium hydride (240 mg, 10 mmol) and tetrahydrofuran (10ml) were placed in an eggplant-shaped flask (50 ml). 2,2-Dimethyl-4carbomethoxytetrahydrofuran-3-one (5-67) (1.755 g, 10 mmol) was slowlydripped to the suspension at 0° C. Hydrogen gas was immediatelygenerated.

The resulting light yellow solution was stirred at 0° C. for 10 minutes,followed by slowly adding 2-(bromomethyl)-biphenyl (2.595 g, 10.5 mmol).After the resulting solution was stirred at room temperature over night,distilled water was added to the solution to cease the reaction.

The solution was extracted with ether (100 ml × 1, 50 ml × 1). The etherlayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated by using an evaporator to obtain a crude product (3.52 g).The crude product was purified by silica gel column chromatography usingn-hexane-ethyl acetate (5:1), thus obtaining the title compound (4-67)(3.07 g, 91.0%).

¹ H-NMR (δppm, CDCl₃): 0.82 (s, 3H), 1.19 (s, 3H), 3.21 (d, lH), 3.52(d, 2H), 3.67 (s, 3H), 4.17 (d, 1H), 7.2-7.3 (m, 6H), 7.36 (t, 1H), 7.42(t, 2H).

[2] Synthesis of 2,2-dimethyl-4-(2-biphenylmethyl)-tetrahydrofuran-3-one (3-67 )

The ketoester compound (4-67) (1.694 mg, 5.01 mmol), 12.5% sulfuric acid(5 ml), and acetic acid (10 ml) were placed in an eggplant-shaped flask(100 ml) and reacted at 130° C. for 8 hours. The reaction was ceased bypouring the solution into distilled water (50 ml) at 4° C.

The resulting solution was extracted with ether (50 ml × 1, 30 ml × 1).The ether layers were washed with a saturated aqueous solution of sodiumhydrogencarbonate and with distilled water, and dried over magnesiumsulfate.

The solvent was removed from the dried solution by using an evaporatorto obtain a crude product (3-67) (1.354 g).

Rf: 0.521 (n-hexane-ethyl acetate = 5:1)

¹ H-NMR (δppm, CDCl₃): 0.994 (s, 3H), 1.083 (s, 3H) 2.42 (d, 2.62 (d,1H), 3.49 (t, 1H) 3.76 (t, 1H), 7.2-7.3 (m, 6H), 7.3-7.4 (m, 3H)

IR (v_(max), cm⁻¹, KBr): 3150m, 3125m, 2971m, 2925m, 2850m, 1740s.

[3] Synthesis of7-(2-phenylbenzyl)-4,4-dimethyl-1,5-dioxaspiro[2.4]heptane (2-67)

Trimethylsulfonium iodide (1.430 g, 6.5 mmol) and DMSO (6 ml) wereplaced in an eggplant-shaped flask (50 ml).

n-Hexane-washed sodium hydride (156 mg, 6.5 mmol) was gradually added at10° C., and the mixture was stirred at room temperature for 30 minutes.

A solution of the ketone compound (3-67) in DMSO (2.0 ml) was slowlyadded to the solution at 10° C., followed by stirring at roomtemperature for 1 hour.

After the end of the reaction had been confirmed, the solution waspoured into ice-cold water to cease the reaction. The solution wasextracted with ether (50 ml × 1, 30 ml × 1). The ether layers werewashed with distilled water (30 ml), and then washed with brine (30 ml ×1). The washed solution was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, thus obtaining a crude product ofthe title compound (2-67) (881.9 mg).

[4] Synthesis of2,2-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)-3-hydroxy-5-(2-phenylbenzyl)-tetrahydrofuran(Compound No. 67).

The epoxide compound (2-67) (881.9 mg. 3.34 mmol), sodium salt of1H-1,2,4-triazole (394.9 mg, 4.34 mmol), and dimethylformamide (5.0 ml)were placed in an eggplant-shaped flask (100 ml).

The mixture was stirred at 70° C. for 2 hours in an atmosphere of argon,poured into cold water, and extracted with ether (100 ml × 1, 50 ml ×1). The ether layers were washed with distilled water and brine, andthen dried over anhydrous sodium sulfate.

The dried solution was concentrated by using an evaporator to obtain acrude product (794.1 mg).

The crude product was recrystallized from ethyl acetate-n-hexane-toobtain the title compound as white crystals (Compound No. 67) (469 mg).

Rf: 0.42 (n-hexane-ethyl acetate =1:4) mp: 150°-151° C.

¹ H-NMR 0.64 (s, 3H), 1.07 (s, 3H), 2.25 (m, 1H), 2.65 (dd, 1H), 2.85(dd, 1H), 3.50 (t, 1H), 3.64 (t, 1H), 3.71 (d, 1H), 3.76 (d, 1H), 7.32(m, 9H), 7.89 (s, 1H), 8.00 (s, 1H)

IR (v_(max), cm⁻¹, KBr): 3425w, 3150s, 2980s, 2900s, 1600w, 1520s,1482s, 1440s, 1423m, 1365m, 1280s, 1202m, 1130s

[5] Synthesis of2,2-dimethyl-3-(imidazol-1-ylmethyl)-3-hydroxy-5-(2-phenylbenzyl)-tetrahydrofuran(Compound No. 68)

The epoxide compound (2-67) (9.21 mg, 3.49 mmol), sodium salt ofimidazole (453 mg, 4.53 mmol), and dimethylformamide (5.0 ml) wereplaced in an eggplant-shaped flask (100 ml), and the mixture was heatedand maintained at 70° C. for 2.5 hours in an atmosphere of argon.

The solution was poured into cold water (50 ml) and extracted with ether(100 ml × 1, 50 ml × 1). The ether layers were washed with brine anddried over anhydrous sodium sulfate. The dried solution was concentratedunder reduced pressure to obtain a crude product (930.5 mg).

The crude product was recrystallized from n-hexane-ethyl acetate toobtain the title compound as white crystals (Compound No. 68) (781.8 mg,69%).

Rf: 0.24 (ethyl acetate ) mp: 92°-95° C.

¹ H-NMR (δppm, CDCl₃): 0.71 (s, 3H), 1.05 (s, 3H), 2.30 (m, 1H), 2.60(dd, 1H), 2.82 (dd, 1H), 3.42 (d, 3.60 (d, 1H), 6.91 (s, 1H), 6.98 (S,1H); 7.27 (m, 9H)

IR (v_(max), cm⁻¹, KBr): 3450m, 3200m, 3000m, 2950m, 2890m, 1600w,1520s, 1484m, 1440m

Example 6: Acute Toxicity

Acute toxicity by oral route was investigated using ICR-JCL mice.

The compounds of the present invention, Compound Nos. 1, 2, 13, 14, 33,34, 41, 42, 47, 48, 53, 54, 67, and 68, were dissolved or dispersed inpolyethylene glycol 200 or physiological saline. The solution orsuspension was given in a prescribed amount by means of a syringe or astomach tube. After administration, intoxication symptoms were observedfor 7 consecutive days to determine lethality and to calculate the LD₅₀value, which was more than 1000 mg/kg for each compound of the presentinvention.

Example 7: Antimycotic Activity

Five-week-old female ICR mice of 10 animals per group were infected withCandida albicans (IFO 1060) in an amount of 4.8×10⁶ cfu (colony formingunit)/mouse through a tail vein.

After one hour following the introduction of the infection, a solutionof each compound (see Table 8 below) in polyethylene glycol 200 wasorally administered for 5 consecutive days in the amount of 100 mg/kgday.

After the end of the administration, mortality was observed for 20 daysand the survival rate and mean survival days were calculated.

The results are shown in Table 8. In Table 8, the solvent group wasadministered only with polyethylene glycol.

                  TABLE 8                                                         ______________________________________                                        Comp. No.     Survival Rate (%)                                               ______________________________________                                         1            40                                                               2            55                                                              13            55                                                              14            70                                                              21            37                                                              22            46                                                              33            60                                                              34            80                                                              41            56                                                              42            63                                                              47            58                                                              48            53                                                              53            42                                                              54            40                                                              67            53                                                              68            62                                                              Control       20                                                              Solvent Control                                                                             20                                                              ______________________________________                                    

Example 8: Aromatase Inhibitory Activity

Aromatase activity was determined in the manner described by Covey, D.F., Biochem. Biophys. Res. Commun. 157 (1), 81-86 (1988).

Aromatase inhibitory activity of the compounds was evaluated in the 50%aromarase-inhibitory concentration (IC₅₀). Microsomes of human-placentaand [19-¹⁴ C]4-androstene-3,17 dione were used as an aromatase sourceand a substrate, respectively.

The radioactivity of H¹⁴ COOH which was released into a reaction mixtureas a result of aromatization was measured to evaluate the aromataseactivity.

The aromatase inhibitory activity and the concentration of each compoundwas depicted in a graph, from which the IC₅₀ was determined.

[19-¹⁴ C]4-Androstene-3,17-dione (1×10⁻⁶ M, 2 KBq/ml), human placentamicrosomes (a protein concentration of 0.1 mg/ml), coenzyme NADP (2×10⁻³M), glucose-6-phosphoric acid (4×10⁻³ M), and glucose-6-phosphoric aciddehydrogenase (4U/ml) were added to a phosphoric acid buffer solution(67 mM, pH 7.2, 0.5 ml) and reacted at 37° C. for 30 minutes while themixture was being shaken.

The test compound dissolved in DMSO was added to the reaction mixtureand the final concentration of DMSO was in the range of 0.1 to 0.55% byvolume per volume.

Chloroform (5 ml) was then added to the reaction mixtures to cease thereaction. The H¹⁴ COOH, which had been released into a reaction mixture,was recovered in a water layer by stirring the reaction mixture. Thewater layer (0.1 ml) was added to a liquid scintillation cocktail(Atomlight, Dupont, 4 ml) to measure its radioactivity.

The results are shown in Table 9. The positive control is4-hydroxyandrostenedione.

                  TABLE 9                                                         ______________________________________                                        Comp. No.       IC.sub.50 (M)                                                 ______________________________________                                         1              6.0 × 10.sup.-6                                          2              5.3 × 10.sup.-7                                         13              5.3 × 10.sup.-6                                         14              4.8 × 10.sup.-7                                         21              4.7 × 10.sup.-6                                         22              6.3 × 10.sup.-7                                         33              7.0 × 10.sup.-6                                         34              5.0 × 10.sup.-7                                         41              3.0 × 10.sup.-6                                         42              2.7 × 10.sup.-7                                         47              1.0 × 10.sup.-6                                         48              1.5 × 10.sup.-6                                         53              1.2 × 10.sup.-6                                         54              1.0 × 10.sup.-6                                         67              4.7 × 10.sup.-6                                         68              3.5 × 10.sup.-7                                         Positive Control                                                                              2.0 × 10.sup.-5                                         ______________________________________                                    

Example 9: Antitumor Effects

Fifty-day-old female Sprague-Dawley rats were orally given7,12-dimethylbenzanthracene (15 mg/kg) and observed for two months.Those rats developing spontaneous mastocarcinoma were selected anddivided into groups each consisting of 15 animals: groups each of whichis to be given a different compound of the present invention; a group tobe given a control compound; and a control group to be given a simplephysiological saline solution. Each group was intraperitoneally giventhe corresponding physiological saline solution or dispersion in anamount of 25 mg/kg daily for 20 consecutive days. Five days after thelast administration, the rats were sacrificed to weigh the tumors. Themean tumor weight (T) of the 15 rats of each of the groups which hadbeen given compounds of the present invention or the control compound,and the mean tumor weight (C) of the 15 rats of the control group whichhad been given a simple physiological saline solution were calculated.The tumor growth inhibition rate of each group was calculated on thebasis of the following formula:

Tumor Growth Inhibition Rate (%) = {1-T/C)} × 100. The results are shownin Table 10. Positive control is 4-hydroxyandrostenedione.

                  TABLE 10                                                        ______________________________________                                        Comp. No.      Inhibition rate (%)                                            ______________________________________                                         1             60                                                              2             54                                                             13             58                                                             14             63                                                             21             72                                                             22             75                                                             33             65                                                             34             80                                                             41             48                                                             42             56                                                             47             55                                                             48             70                                                             53             60                                                             54             73                                                             67             74                                                             68             85                                                             Positive Control                                                                             48                                                             ______________________________________                                    

Example 10: Preparation of Formulation

    ______________________________________                                        Compound No. 1          100 mg                                                Polyoxyethylene Sorbitan Mono-oleate                                                                   50 mg                                                Starch Powder           250 mg                                                ______________________________________                                    

The above ingredients were mixed uniformly and put into a capsule, thuspreparing a capsule containing 100 mg of Compound No. 1.

What is claimed is:
 1. A pharmaceutical composition comprisinganaromarase-inhibiting effective amount of an azole derivative of theformula: ##STR14## including stereoisomers thereof, wherein R₁ and R₂each are H or C₁ -C₄ alkyl; R₃ is H, OH, CN, halogen, haloalkyl, C₁ -C₄alkyl, or phenyl, and if there are two or more R₃ groups, such R₃ groupsmay be the same or different; n is an integer from 0 to 5; Y is CH; andX is O, S, or NH; or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier or diluent.
 2. The pharmaceuticalcomposition of claim 1, wherein R₁ and R₂ each are H, methyl, ethyl,n-propyl, i-propyl, n-butyl, or t-butyl; R₃ is halogen, CN, or phenyl;and n is an integer from 0 to
 2. 3. A method of treatingestrogen-dependent diseases comprising administrating to a patient inneed thereof an estrogen-dependent disease treating effective amount ofan azole derivative of the formula: ##STR15## including stereoisomersthereof, wherein R₁ and R₂ each are H or C₁ -C₄ alkyl; R₃ is H, OH, CN,halogen, haloalkyl, C₁ -C₄ alkyl, or phenyl, and if there are two ormore R₃ groups, such R₃ groups may be the same or different; n is aninteger from 0 to 5; Y is CH; and X is O, S, or NH; or apharmaceutically acceptable salt thereof.
 4. The method of claim 3,wherein R₁ and R₂ each are H, methyl, ethyl, n-propyl, i-propyl,n-butyl, or t-butyl; R₃ is halogen, CN, or phenyl; and n is an integerfrom 0 to 2.